Spiro heterocycles bearing piperidine moiety as potential scaffold for antileishmanial activity: synthesis, biological evaluation, and in silico studies.

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1.

Thiazolidine-2,4-dione-linked ciprofloxacin derivatives with broad-spectrum antibacterial, MRSA and topoisomerase inhibitory activities.

A series of ciprofloxacin/thiazolidine-2,4-dione hybrids 3a-m were prepared and identified by IR, 1HNMR, 13CNMR and elemental analysis. The antibacterial activity results of the designed hybrids revealed a shift of spectrum toward Gram-positive bacteria. They exhibited excellent activity against S. aureus ATCC 6538, with the most potent compounds being 3a, 3e, 3g, 3i, 3k, 3l and 3m possessing MICs of 0.02, 2.03, 0.64, 0.35, 1.04, 0.22 and 0.36 µM, respectively, compared to their parent compound ciprofloxacin (MIC: 5.49 µM). They also showed interesting activity against MRSA AUMC 261 with 3a, 3e and 3l showing MIC values of 5 nM. Reduced activity was observed against Gram-negative bacteria with compound 3l exhibiting a slightly higher activity against K. pneumoniae ATCC10031 with a MIC value of 0. 08 µM. Mechanistically, the incorporation of thiazolidine-2,4-dione ring into ciprofloxacin retained its ability to inhibit DNA synthesis via inhibiting both topoisomerase IV and DNA gyrase of S. aureus. Compounds 3a, 3l and 3m were more potent than ciprofloxacin for topoisomerase IV (IC50 = 0.3-1.9 µM) and gyrase (IC50 = 0.22-0.31 µM) inhibition, which coincide with their antibacterial activity against S. aureus ATCC 6538. Docking against DNA gyrase active site confirmed the ability of the tested compounds to form stable complexes with the enzyme; like that of ciprofloxacin, 3a, 3i, 3k, 3m and 3l reconsidered promising broad-spectrum antibacterial agents targeting topoisomerase IV and gyrase enzymes and have good activity against MRSA.

Synthesis, DFT Calculations, Antiproliferative, Bactericidal Activity and Molecular Docking of Novel Mixed-Ligand Salen/8-Hydroxyquinoline Metal Complexes.

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2'-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, 1H NMR, 13C NMR, UV-VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H2O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H2O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC50 values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC50 values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature.

Ethyl 3-amino-5-anilino-4-cyano-thio-phene-2-carboxyl-ate.

In the title compound, C14H13N3O2S, the dihedral angle between the thio-phene and phenyl rings is 24.95 (8)°. The mol-ecular structure is consolidated by intra-molecular N-H⋯O and C-H⋯S inter-actions. The crystal structure features N-H⋯N and N-H⋯O hydrogen bonds forming centrosymmetric R 2 (2)(12) dimers, which are linked into a two-dimensional network parallel to (011) with an S(6)R 2 (2) S(6) motif. In addition, π-π stacking inter-actions [centroid-centroid distance = 3.7013 (12) Å] occur between the thio-phene and phenyl rings of adjacent mol-ecules.

2,2'-[(1,3,4-Thia-diazole-2,5-di-yl)bis-(sulfanedi-yl)]diaceto-nitrile.

In the title compound, C6H4N4S3, the 1,3,4-thia-diazole ring is essentially planar, with an r.m.s. deviation of 0.001 Å. The two N-C-S-C torsion angles in the mol-ecule are -23.41 (15) and 0.62 (14)°. One aceto-nitrile group is above the plane of the 1,3,4-thia-diazole ring and the other is below it, indicating syn and anti orientations. In the crystal, C-H⋯N hydrogen bonds link the molecules into ribbons along [010].

2-(4-Oxo-3-phenyl-1,3-thia-zolidin-2-yl-idene)propanedi-nitrile.

In the title compound, C12H7N3OS, the five-membered 1,3-thia-zolidine ring is nearly planar [maximum deviation = 0.032 (2) Å] and makes a dihedral angle of 84.14 (9)° with the phenyl ring. In the crystal, mol-ecules are linked by C-H⋯N hydrogen bonds into infinite chains along [-101]. C-H⋯π inter-actions contribute to the arrangement of the mol-ecules into layers parallel to (101).

Synthesis and antimicrobial activity of some novel 1,2-dihydro-[1,2,4]triazolo[1,5-a]pyrimidines bearing amino acid moiety.

A new series of [1,2,4]-triazole bearing amino acid derivatives 2a-d-9a-d were synthesized under green chemistry conditions via multicomponent reaction using lemon juice as an acidic catalyst. The obtained compounds were characterized by different spectral and elemental analyses. The obtained candidates showed promising antibacterial activity against some standard bacteria and multidrug resistant (MDR) clinical isolates. In contrast to the reference drugs cephalothin and chloramphenicol, the tested compounds showed substantial better MIC values towards the tested MDR strains. The most active compounds 3c, 8a and 9d against MDR bacteria were tested for MBC and MIC index, the results indicted the bacteriostatic activity of these compounds. The most active compounds 2c, 2d, 3c, 8a, 8b, 9a, 9b, 9c and 9d showed a high selectivity index towards antimicrobial activity against K. pneumoniae and MRSA1 compared to mammalian cells, suggesting a good safety profile.

Crystal structure of poly[di-µ-aqua-{5-[(1Z)-2-(4-chloro-phen-yl)-1-cyano-ethenyl]-1,2,3,4-tetra-zol-1-ido-κN (1)}sodium].

In the title compound, [Na(C10H5ClN5)(H2O)2] n , infinite chains of [Na(H2O)2](+) cations having a diamond-shaped cross-section and running parallel to the b axis are formed. O-H⋯N hydrogen bonds to the anions generate layers parallel to (100) which have the chloro-benzene-cyano-ethenyl substituents protruding from both surfaces. The sodium ion makes a short contact of 2.4801 (13) Šwith the N atom of the tetra-zolide ring which is syn to the cyano N atom.